The health care professional, prior to an intervention, makes a thorough assessment and applies interventions to optimize the patient's journey. 

A comprehensive preoperative evaluation involves:

• Medical and physical history: identify preexisting conditions that could affect the outcome of the intervention, such as cardiovascular disease, diabetes, obesity, and tobacco use.
• Laboratory and diagnostic tests: routine blood tests, renal and liver function assessments, and, if necessary, cardiopulmonary tests to assess the patient's ability to withstand anesthesia and surgery.
• Consultations: involve specialists such as cardiologists, pulmonologists, or endocrinologists for patients with significant comorbidities.
• Nutritional assessment: identify patients who are malnourished or at risk of malnutrition, as malnutrition may increase the risk of postoperative complications.
• Nutritional interventions: in malnourished patients, consider preoperative nutritional supplementation to improve protein and calorie reserves.
• Optimization of medical conditions: make sure conditions such as hypertension, diabetes, and chronic lung disease are well controlled before surgery.
• Medication management: review and adjust preoperative medications, especially anticoagulants, antiplatelet and diabetes medications, in consultation with treating physicians.
• Infectious Risk Reduction Planning.
  • Antibiotic prophylaxis: administer appropriate prophylactic antibiotics before incision to reduce the risk of surgical site infection.
  • Bowel preparation: evaluate the use of mechanical and antibiotic bowel preparation according to the latest indications and center practice.
• Pain Management and Anesthesia Techniques: implement multimodal pain management strategies that may include nerve blocks, non-opioid medications, and loco-regional anesthesia techniques to reduce the use of opioids and promote faster recovery.
• Fluid therapy: use a restrictive approach to fluid management to avoid fluid overload, which can adversely affect surgical outcomes.
• Enhancement of Physical Abilities
  • Early mobilization: encourage early postoperative mobilization to prevent complications such as deep vein thrombosis, pneumonia, and muscle atrophy.
  • Preoperative rehabilitation: consider programs to improve patients' physical fitness before surgery.
• Use of Enhanced Recovery After Surgery (ERAS) Protocols.
  • Implementation of ERAS: Adopt ERAS protocols that include several of the elements described above to reduce surgical stress and promote faster and safer recovery.

Carefully planned perioperative evaluation and optimization are essential for the management of patients undergoing major colorectal surgery. Adopting a multidisciplinary approach and using evidence-based protocols, such as those of ERAS, can significantly improve outcomes and reduce the length of hospitalization.

Prof. Massimiliano Varriale

Anastomotic leakage represents one of the most serious postoperative complications in colorectal surgeries, with significant implications for patient morbidity and mortality. Recently, research has begun to explore the impact of the gut microbiome on this risk, suggesting a potentially critical link that could influence future clinical practices.

The gut microbiome is composed of billions of bacteria, viruses, fungi and other microorganisms living in the gastrointestinal tract. This complex ecosystem plays crucial roles not only in digestion, but also in modulating the immune system, protecting against pathogens, and producing essential vitamins and neurotransmitters. Alterations in this delicate balance, known as dysbiosis, have been linked to a variety of pathological conditions, including inflammatory bowel disorders, obesity, diabetes, and, more recently, post-surgical complications such as anastomotic leakage.

Anastomotic leakage occurs when the surgical union between two segments of the intestine fails to heal properly, leading to dehiscence that can cause severe infection and further complications. Recent studies have begun to investigate how the microbiome may influence this healing process:

1. Regulating the immune response: The gut microbiome modulates the local and systemic immune response. A balanced microbiome helps maintain a controlled inflammatory response, which is crucial for healing anastomoses. Conversely, a dysbiosis can lead to an exaggerated or inadequate inflammatory response, compromising healing.
2. Producing bioactive substances: Gut bacteria produce a variety of metabolites, such as short-chain fatty acids (SCFAs), which can have protective effects on the intestinal mucosa and promote healing. Reduced production of these compounds can decrease mucosal resistance and alter tissue regeneration.
3. Interaction with pathogens: A healthy microbiome can suppress the growth of pathogens through competition for nutrients and adhesion sites, as well as through the production of antimicrobial substances. Alteration of this dynamic can facilitate infection at the anastomotic site.

Recent studies have examined the specific role of certain bacterial strains and their association with the risk of anastomotic leakage. For example, a higher abundance of certain pro-inflammatory bacteria correlates with an increased risk of dehiscence. These findings open the way for potential preoperative interventions, such as modulation of the microbiome through probiotics, diet, or other microbial therapies, to improve surgical outcomes.

The impact of the gut microbiome on anastomotic leakage is an emerging field of research that promises to revolutionize approaches to colorectal surgeries. As the understanding of these mechanisms continues to evolve, it is clear that the microbiome plays a significant role in the success of surgical procedures and overall patient health. Future studies will be crucial to develop strategies aimed at optimizing the preoperative microbiome and reducing the risk of postoperative complications such as anastomotic leakage.

Prof. Massimiliano Varriale

The surgical management of patients with cirrhosis presents unique challenges, especially when it comes to interventions in the gastrointestinal tract, such as colorectal surgery. Cirrhosis can compromise several vital body functions, including blood coagulation, liver function, and the immune system. Therefore, it is critical to carefully consider the implications and strategies to optimize surgical outcomes in these patients.

Before referring a cirrhotic patient for colorectal surgery, a comprehensive evaluation to assess the degree of liver damage and associated complications is essential. This evaluation should include:

Assessment of Liver Function:

• Measurement of Child-Pugh score to assess the degree of impaired liver function.
• Extensive laboratory tests to assess liver function, including bilirubin, albumin, prothrombin time (PT), and platelet count levels.
• Assessment of nutritional status and the presence of malnutrition, which may be common in cirrhotic patients.
• Bleeding Risk Assessment
• Evaluation of platelet function and coagulation factors, as cirrhotic patients are at risk for bleeding and coagulopathy.
• Exclusion of Treatable Etiologies
• Exclusion of treatable causes of cirrhosis, such as viral hepatitis infection, when possible.

During colorectal surgery, there are several considerations to keep in mind:

Management of Hemostasis

• Use of techniques to minimize the risk of bleeding and bleeding complications.
• Careful monitoring of coagulation during surgery.

Venous Pressure Control

• Cirrhosis can lead to portal hypertension, so it is important to monitor and manage venous pressure during surgery to prevent bleeding and hemodynamic complications.

Postoperative Management

• Close monitoring in postoperative intensive care unit, if indicated.
• Consideration of liver supportive therapies, such as albumin, if needed.

Cirrhotic patients undergoing colorectal surgery are at increased risk of postoperative complications, including infection, bleeding, and liver failure. Prognosis depends on the extent of cirrhosis, residual liver function and the effectiveness of peri-operative support. Colorectal surgery in cirrhotic patients requires a multidisciplinary approach and detailed risk assessment. Optimal management requires close collaboration among critical support specialists. 

Prof. Massimiliano Varriale

Colorectal cancer surgery requires careful pain management to improve postoperative recovery and reduce complications. The anesthetic approach can have a significant impact on patient recovery and long-term outcomes. We review here three main anesthetic strategies: traditional opioid use, low-opioid techniques, and completely opioid-free strategies.

Traditional opioid-based anesthesia is widely used for its effectiveness in controlling acute pain. Opioids, such as morphine, fentanyl and oxycodone, provide immediate and potent relief, which is essential in the immediate postoperative phases of major surgery.

Advantages:

• Effective and rapid pain control.
• Wide experience and familiarity among anesthesiologists.

Disadvantages:

• Risk of respiratory depression.
• Possible side effects such as nausea, vomiting, constipation, and itching.
• Potential for the development of tolerance or dependence.

Low Opioid Content Anesthesia

This approach seeks to minimize opioid use by combining small doses with other analgesics, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and calcium channel blockers. The goal is to reduce the side effects of opioids while maintaining adequate pain control.

Advantages:

• Fewer side effects than high opioid regimens.
• Reducing the risk of addiction.
• Improved early mobilization and resumption of bowel function.

Disadvantages:

• Potentially less effective for severe pain without optimal adjustment of dosage and drug combination.

Anaesthesia Without Opioids

Opioid-free anesthesia uses non-opioid alternatives to manage pain, such as lidocaine IV, ketamine, magnesium and regional nerve blocks. This strategy is geared toward faster recovery and reduced hospital stay time.

Advantages:

• Elimination of risks associated with opioids, including gastrointestinal and respiratory side effects.
• Potentially shorter hospitalization time.

Disadvantages:

• Challenges in controlling severe pain, especially in patients with high pain threshold.
• Needs staff experienced in advanced anesthetic techniques.

The choice of anesthetic approach in colorectal cancer surgery depends on many factors, including the nature of the surgery, the patient's preexisting conditions, and the skills of the anesthetic team. While opioid use continues to be a mainstay for the control of severe pain, low-opioid and opioid-free strategies are gaining popularity as effective alternatives that can offer significant benefits in terms of recovery and reduction of side effects. Multidisciplinary collaboration in anesthesia planning can help personalize pain treatment, maximizing patient benefits and optimizing surgical outcomes.

Prof. Massimiliano Varriale

University of Federico II Naples

Bottom up suprapubic approach for robotic right hemicolectomy
in right colon cancer

Student: Dr Massimiliano Varriale
Speaker: Prof. Marco Milone

My work

PROCTOLOGIC AND PELVIC FLOOR SURGERY FOCUS ON: TECHNIQUES AND TECHNOLOGIES IN THE TREATMENT OF FISTULAS

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Grafting stem cells taken from autologous adipose tissue has been shown to be a significant contribution in the treatment of some of the complications related to chronic intestinal diseases. Explaining mode of execution, advantages and future prospects of this minimally invasive surgical technique is Massimiliano Varriale, a proctologist at Sandro Pertini Hospital in Rome, who with his team has been employed for years in the research and study of this treatment.

Varriale, proctologist: stem cells may prevent ostomy packing

Stem cells are specialized cells in the human body that have the unique ability to transform into different types of specialized cells. They can self-renew through cell division and are critical for the growth, repair, and maintenance of tissues in the body.

Mesenchymal stem cells are a type of adult stem cell that can differentiate into a variety of cell types, including bone, cartilage, fat and other cells. They are found in various tissues of the body, including bone marrow, adipose tissue, and connective tissue. Mesenchymal stem cells have demonstrated therapeutic potential in several areas, including regenerative medicine, where they can be used to promote regeneration of damaged tissues and to modulate the inflammatory response. They are, at present, the subject of clinical research.

Inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis) are part of the chronic bowel diseases. They can cause symptoms such as abdominal pain, diarrhea, constipation, bloating and bleeding and often require long-term treatment to manage symptoms and improve quality of life.

Fistulas are a common complication of Crohn's disease

In Crohn's disease, inflammation can cause damage to the intestinal lining and lead to the formation of fistulas that connect the intestine with other structures, such as other parts of the bowel, the skin, or other organs. These fistulas can cause symptoms such as abdominal pain, abnormal secretions, and recurrent infections. Treatment of fistulas in Crohn's disease can range from medications to reduce inflammation to surgery to close fistulas and repair intestinal damage.

Why do we talk about inflammatory bowel disease and stem cells? Stem cells are being researched specifically for the treatment of fistulas; including those associated with inflammatory bowel disease. Mesenchymal stem cell transplantation can be considered as a new approach for the treatment of these diseases.

[...]

Full article on nurse24.it

Gut dysbiosis is a condition of imbalance in the composition and function of the microbiota, that is, the "bacterial flora," that collection of microorganisms living inside our intestines. These microorganisms are bacteria, viruses and fungi present in our intestinal mucosa.Many of these microorganisms perform beneficial functions by helping us in defense against infection by harmful microbes, contributing to the synthesis of useful substances and the production of new molecules for our body. Each individual has his or her own microbiota, and the total number of genes in it is one hundred times that of the human genome. The balance of the microbiota is essential for managing the well-being of our body, especially in the following conditions:

• Digestive/intestinal disorders
• Overweight/hunger and satiety control
• Pregnancy/lactation
• Menopause/osteoporosis
• Energy production/muscle development
• Skin disorders
• Anxiety, stress, insomnia

Dysbiosis can be caused by an overgrowth of "bad" bacteria within the gut, which causes its irritation and can affect our daily well-being.

There are many causes that can give rise to dysbiosis; among the most common and general ones we have poor diet, psychophysical stress, drug abuse (antibiotics and anti-secretors) and age, as well as specific pathological conditions of the gastro - intestinal tract, chronic inflammatory diseases, obesity, tumors and colitis.

Dysbiosis is mainly manifested by abdominal pain, bloating, meteorism, flatulence, diarrhea, or constipation. The irritation caused by dysbiosis, in fact, can lead to digestive disorders and some indirect food intolerances, that is, those not directly related to a specific food. This is caused by inflamed intestinal villi that can no longer absorb all the substances we ingest. To intervene on this type of intolerance, it is necessary to treat the inflammation caused by dysbiosis.

To diagnose dysbiosis, and thus be able to intervene with specific treatment, there are laboratory tests that are based on the analysis of the strains of bacteria that are present in the stool. 

To treat and/or prevent dysbiosis, one must first act by following a proper diet, low in sugar and fat and rich in fiber, vitamins (such as vitamin D) and polyphenols.
In addition to diet, a crucial role in remodeling the gut microbiota is played by a healthy lifestyle: regular physical activity, stress management, proper sleep time, and avoidance of smoking and alcohol. It is
also possible to rebalance the gut microbiota through the intake of probiotics, that is, beneficial bacteria such as Lactobacilli and Bifidobacteria.

Some studies have shown that a condition of dysbiosis, with proliferation of pathogenic bacterial species, such as those responsible for bacterial vaginosis (e.g., Gardenella V.), could promote the cycle of viral replication, persistence of HPV infection and neoplastic transformation.

Prof. Massimiliano Varriale

The purpose of the evidence-based guidelines is to present a consensus position by members of the Italian Unitary Society of Colon-Proctology (SIUCP: Società Italiana Unitaria di Colon-Proctologia) on the diagnosis and management of anal fissure, with the aim of guiding each physician in choosing the best treatment option, in accordance with the available literature.

A group of experts was designed and commissioned by the SIUCP Board to develop key questions on the main topics concerning the management of anal fissures and to perform a thorough search on each topic in several databases in order to provide evidence-based answers to the questions and summarize them in statements.

All clinical questions were discussed by the expert panel in different rounds through the Delphi approach, and for each statement, a consensus was reached among the experts. The questions were created according to PICO criteria, and the statements were developed by adopting the GRADE methodology.

In patients with acute anal fissure, medical therapy with dietary and behavioral regulations is indicated. In the chronic phase of the disease, conservative treatment with topical nifedipine 0.3 percent plus lidocaine or nitrates 1.5 percent may be the first-line therapy, possibly combined with ointments with film-forming, anti-inflammatory and healing properties such as Propionibacterium extract gel. If first-line treatment fails, the surgical strategy (internal sphincterotomy or fissurectomy with flap), may be guided by clinical findings, possibly supported by endoanal ultrasound and anal manometry.

In patients with anal fissure, what are the appropriate morphological investigations?

• Based on the limited available literature, no recommendation can be made regarding the use of imaging investigations in patients with typical acute anal fissure, especially in the presence of anal pain and spasm that make it difficult to perform any endoanal examination.
• In patients with atypical anal fissures, especially when associated pathology including inflammatory bowel disease or colorectal and anal cancer is suspected, imaging investigations such as colonoscopy, anoscopy, and endoanal ultrasound may be useful for diagnostic purposes (weak recommendation based on low-quality evidence, 2C).
• In patients with chronic anal fissure poorly responsive to medical therapy, in order to assess the presence of associated occult anal sepsis, morphologic evaluation with endoanal ultrasound may be considered (weak recommendation based on low-quality evidence, 2C).
• In patients with chronic anal fissure and suspected occult local sepsis, if endoanal ultrasound is not available, MRI may be considered as an alternative diagnostic tool (expert opinion)

In patients with anal fissure, what are the appropriate functional investigations?

• Based on the available literature, no recommendation can be made regarding the use of functional investigations such as anorectal manometry in patients with acute anal fissure. Commonly, anorectal physiology tests are not routinely performed at this juncture, and the initial assessment of sphincter hypertonia in patients with anal fissure could be based on clinical examination (expert opinion).
• In patients with chronic anal fissure poorly responsive to medical therapy, in order to accurately select patients without internal sphincter hypertonia, an anorectal manometric evaluation may be considered (weak recommendation based on low-quality evidence, 2C).
• Although anal manometry can detect anal tone more accurately than digital rectal exploration, this functional investigation is not always feasible in patients with chronic hyperalgesic fissure. If manometry is not feasible or available, assessment of anal tone with digital examination may be considered sufficient (expert opinion)

In patients with acute anal fissure, what is the treatment of choice?

• In patients with acute anal fissure, nonsurgical management should be considered as first-line treatment, while surgical treatment can be considered in the chronic phase, in patients who do not respond after at least 6 weeks of conservative treatment (strong recommendation based on moderate-quality evidence, 1B).
• Nonsurgical management in patients with acute anal fissure should include warm semicups and increased dietary fiber and water intake until soft stools are achieved (strong recommendation based on moderate-quality evidence, 1B).
• In cases of persistent hard stools, fiber supplements and mass-forming laxatives can be added to therapy (expert opinion)
• In patients with acute anal fissure, adjunctive therapy with topical application of sphincter relaxants such as calcium channel blockers and, in particular, 0.3 percent nifedipine plus 1.5 percent lidocaine may be considered in case of poor patient adherence to dietary and behavioral medical prescriptions (weak recommendation based on low-quality evidence, 2C).
• Supplementation of topical metronidazole in the nonsurgical management of acute anal fissure may be considered (weak recommendation based on low-quality evidence, 2C).
• The additional use of common analgesic drugs, topical anesthetics, and ointments with thermogenic and muscle relaxant effect in the treatment of acute anal fissure is reasonable in case of inadequate pain control (expert opinion).
• In cases of acute hyperalgesic anal fissure not responsive to common pain relievers and ointments, a surgical approach may be considered in emergency settings (expert opinion)
• Self-induced gradual mechanical anal dilation with dedicated plastic dilators is commonly suggested and prescribed for patients with anal sphincter hypertonia and spasm. However, due to the lack of relevant literature, it is not possible to make recommendations regarding this treatment in patients with anal fissure.

In patients with chronic anal fissure, what is the first-line treatment?

• In patients with chronic anal fissure and typical clinical presentation (severe anal pain associated with suspected anal sphincter hypertonia on objective examination), topical application of calcium channel blockers or nitrates (0.4% glyceryl trinitrate) may be the first-line treatment (strong recommendation based on moderate-quality evidence, 1B).
• Topical use of calcium channel blockers is associated with similar efficacy and fewer side effects, compared with nitrates. (Strong recommendation based on moderate-quality evidence, 1B).
• In patients with chronic anal fissure and typical clinical presentation, topical therapy of 0.3% nifedipine plus 1.5% lidocaine may be considered as first-line therapy (weak recommendation based on moderate-quality evidence, 2B).
• The additional use of topical ointments with curative properties in the treatment of chronic anal fissure may be reasonable in combination with topical calcium channel blockers and nitrates in cases of anal sphincter hypertonia or as an exclusive treatment in cases of anal sphincter hypotonia (expert opinion).
• Among topical ointments with film-forming, anti-inflammatory and healing properties, Propionibacterium extract gel (PeG) may be considered (weak recommendation based on moderate-quality evidence, 2B).

In patients with chronic anal fissure, what is the role of botulinum toxin injection?

• In patients with chronic anal fissure, botulinum toxin injection shows comparable results to topical nitroglycerin as first-line therapy (strong recommendation based on moderate-quality evidence, 1B).
• In patients with chronic anal fissure, botulinum toxin injection may be considered as second-line therapy after unsuccessful treatment with topical nitrates (weak recommendation based on low-quality evidence, 2C).
• The use of botulinum toxin injection in patients with chronic anal fissure is limited by the low uptake of the procedure and the heterogeneity of injection protocols adopted (expert opinion).

In patients with chronic anal fissure what is the role of anal dilatation?

• Uncontrolled anal dilatation is associated with a lower cure rate and higher risk of incontinence when compared with lateral internal sphincterotomy and therefore cannot be recommended (strong recommendation based on moderate-quality evidence, 1B)
• Pneumatic balloon dilation may be offered as a treatment option in patients with chronic anal fissure poorly responsive to medical therapy and associated with anal hypertonia (weak recommendation based on moderate-quality evidence, 2B)
• In the context of chronic anal fissure associated with anal hypertonia, pneumatic ballon anal dilatation may be preferred to sphincterotomy in multiparous female patients and in patients with previous documented sphincter damage or obstetric injury (weak recommendation based on moderate-quality evidence, 2B)

In patients with chronic anal fissure what is the role of sphincterotomy?

• Lateral internal sphincterotomy may be offered as a treatment option in patients with chronic anal fissure poorly responsive to medical therapy and associated with anal hypertonia (strong recommendation based on high-quality evidence, 1A).
• Within this group of patients, lateral internal sphincterotomy should be considered as the treatment of choice in individuals with no clinical complaints of fecal incontinence, no previous anorectal operations or trauma, and no previous sphincter injury or obstetric trauma (strong recommendation based on high-quality evidence, 1A).
• Lateral internal sphincterotomy should not be offered to patients with fecal incontinence at baseline or with a documented anal sphincter injury or obstetric trauma (strong recommendation based on high-quality evidence, 1A).
• Open and closed lateral internal sphincterotomy techniques show similar results (strong recommendation based on high-quality evidence, 1A).

What is the appropriate extent of sphincterotomy?

• A safe lateral internal sphincterotomy should be confined below the level of the serrated line (strong recommendation based on moderate-quality evidence, 1B)
• Lateral internal sphincterotomy adapted to the slot length is equally effective and safer than conventional sphincterotomy extended to the serrated line (strong recommendation based on high-quality evidence, 1A)
• In female patients, the ideal extension of the internal sphincter division should be between 5 and 9 mm of muscle, never exceeding 10 mm (strong recommendation based on low-quality evidence, 1C)

In patients with chronic anal fissure, what is the role of fissurotomy and fissurectomy?

• Based on the limited available literature, no recommendation can be made regarding the use of fissurotomy in the treatment of chronic anal fissure.
• Fissurectomy is inferior to lateral internal sphincterectomy in the treatment of chronic anal fissurectomy associated with internal anal sphincter hypertone (strong recommendation based on high-quality evidence, 1A)
• Fissurectomy may be considered in patients with chronic anal fissure associated with abscess or fistula and normotonic internal anal sphincter (weak recommendation based on low-quality evidence, 2C)

In patients with chronic anal fissure what is the role of the anocutaneous flap?

• In light of the low postoperative risk of incontinence, the anocutaneous flap may be considered as an alternative surgical option in patients with chronic anal fissure and high risk of incontinence after sphincterotomy (low anal pressure at rest, previous anal surgery or trauma, previous documented sphincter injury or obstetric trauma) (weak recommendation based on moderate-quality evidence, 2B).
• Adding an anocutaneous flap to sphincterotomy or botulinum toxin injection can reduce postoperative pain, improve healing rate, and reduce the rate of postoperative incontinence (weak recommendation based on low-quality evidence, 2C).

In patients with chronic anal fissure, what is the role of tibial nerve stimulation?

• Percutaneous tibial nerve stimulation may be considered as a potential alternative treatment for chronic anal fissure (weak recommendation based on low-quality evidence, 2C).
• Percutaneous tibial nerve stimulation may be considered as a potential treatment option for chronic anal fissure resistant to other conservative measures in patients who are unfit for surgery or who refuse surgical treatment (expert opinion)

Prof. Massimiliano Varriale

Stem cells have attracted great interest in the field of medicine because of their unique abilities to regenerate and differentiate into various specialized cell types. In proctology, the use of stem cells offers promising prospects for treating a variety of diseases of the lower gastrointestinal tract. This article will explore the potential applications of stem cells in proctology, along with related challenges and ethical issues.

Proctology is a branch of medicine that deals with diseases of the rectum and anus. Some of the most common conditions treated by proctologists include hemorrhoids, anal fissures, anal fistulas, fecal incontinence, and rectal cancers. Although there are several therapeutic options for these diseases, the use of stem cells offers new possibilities for improving clinical outcomes.

Stem cells have the ability to self-regenerate and differentiate into specific cells, making them valuable for treating conditions where tissue regeneration is needed. In proctology, the use of stem cells to treat the following conditions is being explored:

• Hemorrhoids: Stem cells can be used to regenerate damaged hemorrhoid tissue and reduce the discomfort associated with this condition.
• Anal fissures: Stem cells can help heal anal fissures and promote reconstruction of damaged tissue.
• Anal fistulas: Insertion of stem cells can help promote closure of anal fistulas and promote healing of the surrounding tissue.
• Fecal incontinence: Stem cells can be used to regenerate pelvic floor muscle tissue and improve sphincter control.
• Rectal Tumors: Stem cells could be a promising therapeutic option in the treatment of rectal cancers, enabling greater selectivity and precision.

Stem cells open new perspectives in proctology, offering potential solutions for lower gastrointestinal diseases that until recently had limited therapeutic options. However, addressing challenges related to safety, clinical efficacy, and ethical issues is critical to the safe and effective development of these innovative therapies. With further research and greater understanding of stem cells, we could see significant advances in the management of proctologic conditions and improve the quality of life of patients with these conditions.

Prof. Massimiliano Varriale

Combination chemotherapy with or without targeted therapy is the key treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of cancer cells, it is difficult to make breakthroughs in traditional strategies. Immune checkpoint blockade (ICB) therapy has made significant progress in the treatment of advanced malignancies, and patients who benefit from this therapy can achieve a durable response.

Unfortunately, immunotherapy is only effective in a limited number of patients with high microsatellite instability (MSI-H), and initial segment responders may later develop acquired resistance. As of September 4, 2014, the first anti-PD-1 / PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for second-line mCRC treatment in 2017.

Immunotherapy has developed rapidly in the past 7 years. Extensive research of ICB treatment has indicated that the immunoresistance mechanism of colorectal cancer has gradually become clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are being actively conducted in order to produce lasting effects for patients with mCRC.

Immune checkpoint inhibitor therapy is relatively less toxic than chemotherapy and targeted therapy. However, some of its unique adverse effects reduce its clinical efficacy, and some rare adverse effects could be life-threatening, resulting in skin, endocrine, liver, gastrointestinal, lung, and skeletal muscle toxicity.

ICBs have been successfully used in the MSI-H CRC population. Pembrolizumab, Nivolumab, and Ipilimumab have been approved for use in refractory MSI-H mCRC, and Pembrolizumab has been recommended as first-line treatment therapy.

More recently, clinical trials have indicated that neoadjuvant immunotherapy may have the potential to become the standard therapy for patients with CRC. In a stepwise exploration, ICBs hold promise as adjuvant therapies for patients with stage III CRC after resection.

In addition, combination with specific drugs is expected to improve efficacy and mitigate associated toxicity. The urgent task is to find more biomarkers and formulate standardized scoring standards in order to select the population and benefit more patients.

In addition to microsatellite status, other potential biomarkers can be developed that can help identify potential populations. More importantly, it is significant to develop measures that can turn "cold tumor" into "hot tumor" so as to expand the scope of immunotherapy. This area of research may provide a milestone in the treatment of CRC.

The purpose of immunotherapy is to stimulate the body's immune system response against cancer cells by targeting specific genetic features.

Patients who have the V600E mutation of the BRAF gene (10-15%) may benefit from the combination of encorafenib (Braftovi®) and cetuximab (Erbitux®) even after a failed attempt with another therapy.

Overexpression of another gene (HER2 neu) is present in 3-5% of colon cancers. Interesting therapeutic results have also been obtained for this alteration with the combination of trastuzumab (Herceptin®) and pertuzumab (Parjeta®) and with trastuzumab deruxetan (Enhertu®). These are treatment options currently available only at highly specialized centers.

Prof. Massimiliano Varriale

The use of telemedicine to make remote diagnosis and treatment is becoming increasingly necessary.

Telemedicine involves the secure transmission of medical information and data in the form of text, sound, images or other forms necessary for the prevention, diagnosis, treatment and subsequent follow-up of patients. Telemedicine services should be equated with any diagnostic/therapeutic health service. However, Telemedicine service does not replace traditional health care service in the personal doctor-patient relationship, but complements it to potentially improve effectiveness, efficiency and appropriateness. Telemedicine must also comply with all the rights and obligations inherent in any health care act.

The use of telemedicine, through the remote care and monitoring of patients, offers the appropriate health care response to the needs of a population that is experiencing significant aging and an increase in chronic diseases.

Telemedicine is an indispensable element of the restructuring and rationalization of the health care system, through the use of advanced technologies and new organizational models of home care.

The term telemedicine refers to the whole set of health care services in which, thanks to the use of innovative technologies, the health professional and the patient are not in the same place.

Telemedicine makes it possible to:

• assist and make follow-up visits to patients
• remotely monitor vital parameters of patients
• bring health care professionals into dialogue for consultations on particular clinical cases
• send and receive documents, diagnoses and reports.

Telemedicine is especially indispensable for categories of people who require continuous care, as, for example, they suffer from chronic diseases. These patients may need constant monitoring of certain vital parameters to reduce the risk of onset of complications.

In this case, a better service can be provided to the patient, through faster availability of information on the state of his or her health, allowing to increase the quality and timeliness of health professionals' decisions, particularly useful in emergency-urgency conditions. In this regard, technology and telecommunications play a key function as they help improve the efficiency and safety of care, as well as the confidentiality and protection of patients' personal data.

Telemedicine, which is one of the main areas of application of eHealth, offers highly relevant potential especially for:

• increasing equity in access to social and health services in remote territories, thanks to the decentralization and flexibility of services rendered, the delivery of which is made possible by innovative forms of home care
• redistribute human and technological resources among different principals, making it possible to cover the need for professional skills that are often lacking and ensure the continuity of care in the territory
• offer, through the availability of teleconsultation services, support for mobile emergency services or for remote areas, through the reorganization of health services, possibly through the use of remote clinical resources, including those deployed directly on board ambulances.

Under Mission 6 Health, envisioned in the National Recovery and Resilience Plan (NRP), telemedicine takes a primary role through specific areas of focus. In this reorganization, digital solutions can play a key role in reducing waiting times for visits, improving accessibility to health services, and generally increasing the efficiency of the health system.

The minimum telemedicine services envisaged in the NRP, in order to ensure their uniform activation throughout the country, are:

• Telehealth
• Teleconsultation and medical teleconsultation
• Telecare
• Telemonitoring.

Prof. Massimiliano Varriale

Mesenchymal stem cell (MSC) therapy is a new treatment strategy for cancer and a wide range of diseases with an excessive immune response such as ulcerative colitis (UC), due to its potent immunomodulatory properties and its ability to regenerate and repair tissues. One of the promising therapeutic options may focus on MSC-secreted exosomes (MSC-Exo), which have been identified as a type of paracrine interaction.

Exosomes derived from various sources of MSCs, including human umbilical cord-derived MSCs (hUC-MSCs), human adipose-derived MSCs (hAD-MSCs), human bone marrow-derived MSCs (hBM-MSCs), and olfactory ecto-MSCs (OE-MSCs), have demonstrated the protective role against UC and CRC.

Exosomes from hUC-MSCs, hBM-MSCs, AD-MSCs and OE-MSCs were found to enhance experimental UC through suppressing inflammatory cells, including macrophages, Th1/Th17 cells, reducing the expression of proinflammatory cytokines, as well as inducing the anti-inflammatory function of Treg and Th2 cells and enhancing the expression of anti-inflammatory cytokines. In addition, hBM-MSC-Exo and hUC-MSC-Exo containing tumor suppressor miRs (miR-3940-5p/miR-22-3p/miR-16-5p) have been shown to suppress the proliferation, migration and invasion of CRC cells through the regulation of RAP2B/PI3K/AKT and ITGA2/ITGA6 signaling pathway.

MSC-Exo can exert beneficial effects on UC and CRC through two different mechanisms, including modulation of immune responses and induction of antitumor responses, respectively.

Prof. Massimiliano Varriale

Aspirin is a well-known oral medication widely used as an analgesic and antipyretic drug. In addition, it has been applied to prevent and treat cancer. The classic anti-cancer mechanism of aspirin is to inhibit the activity and inflammation of COX enzymes. In addition, aspirin could inhibit cancer progression by reducing glycolytic levels in tumors. Salicylate is the metabolite of aspirin that could activate AMPK (5'adenosine monophosphate-activated protein kinase) signaling, which further inhibits mTOR signaling and suppresses energy metabolism, including glycolysis. It has been reported that aspirin under directly regulates the level of ENO1, PDK1 and PFKFB3 to attenuate glycolysis and tumor progression. In CRC, several preclinical studies have explored the potential antitumor mechanisms of aspirin.

Clinical studies have demonstrated the potent effect of aspirin in preventing CRC. A double-blind, randomized, placebo-controlled clinical trial of Asian patients with colorectal adenomas and adenocarcinomas indicated that aspirin use (100 mg/day for 2 years) significantly reduced colorectal cancer recurrence (OR = 0.6). Similarly, another clinical trial revealed that daily aspirin use in patients with CRC can reduce adenoma recurrence. Long-term intake of 600 mg of aspirin daily also substantially inhibited cancer occurrence in patients with Lynch syndrome.

However, some studies showed no significant effect of aspirin on the treatment of patients with CRC, pointing to genetic differences in patients, thus highlighting that the application of aspirin requires precise identification of individuals.

To date, a total of 41 clinical trials using aspirin in CRC are listed at https://www.clinicaltrials.gov/, and most clinical trials focus on identifying the effect of aspirin in preventing CRC and the risk category most likely to benefit from aspirin use.

Prof. Massimiliano Varriale

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related death worldwide. Countless CRC patients experience disease progression. As a hallmark of cancer, the Warburg effect promotes cancer metastasis and remodels the tumor microenvironment, including promoting angiogenesis, immune suppression, cancer-associated fibroblast formation, and drug resistance. Targeting Warburg metabolism would be a promising method for the treatment of CRC. In this review, we summarize information on the roles of the Warburg effect in the tumor microenvironment to elucidate the mechanisms governing the Warburg effect in CRC and to identify new targets for therapy.

Tumor cells use many nutrients to sustain proliferation and endless growth. This requires reprogramming of energy metabolism, which is considered one of the hallmarks of cancer. In addition, alteration of energy metabolism leads to nutritional deficiencies and accumulation of metabolic wastes, affecting the biological behavior of neighboring noncancer cells. During the process of glycolysis, cells break down glucose to produce pyruvate and a small amount of ATP. In normal cells with sufficient oxygen levels, pyruvate could enter the tricarboxylic acid (TCA) cycle to generate abundant energy, while cancer cells show high glycolysis activity regardless of oxygen levels and produce lactate through activation of lactate dehydrogenase (LDH) and inhibition of pyruvate metabolism in mitochondria. This phenomenon was first observed by Otto H. Warburg in the early 20th century and called the Warburg effect or aerobic glycolysis. Aerobic glycolysis could meet the energy and nutritional requirements essential for the severe conditions of cancer cell life for cancer progression. The role of glycolytic metabolism in cancer cells and the nearby tumor microenvironment is complex and diverse

Cancer metabolism fuels and drives cancer development. The Warburg effect is the first metabolic feature found in tumors and is continuously evolving giving new insights to treat cancer. In this review, we summarized the crosstalk between Warburg metabolism and CRC, highlighting the irreplaceable role of glycolysis in promoting CRLM and remodeling the tumor microenvironment. The extensive regulation of glycolysis in the development of CRC makes it a potential therapeutic target. Along with the development of classical small molecule inhibitors, dietary intervention studies are increasing survival rates of cancer patients and emerging as a new field of study. The rapid increase in immunotherapy promotes the development of immunometabolism, and emerging evidence has shown the potential to target glycolysis and improve the efficiency of immunotherapy. CRLM and immunosuppression in MSS CRC are two challenges in the treatment of CRC. Therefore, future drug design should focus on maximizing inhibition of tumor and immunosuppressive cells while trying to avoid damage to normal and anti-tumor immune cells. In addition, it is also important to encourage medical organizations to perform clinical trials based on glycolysis.

Prof. Massimiliano Varriale

Ulcerative colitis is a relapsing and remitting disease that is increasing in incidence and prevalence. Treatment is aimed at achieving rapid resolution of symptoms, healing of the mucosa and improvement of the patient's quality of life. Drugs with 5-aminosalicylate acid remain the first-line treatment for mild to moderate disease. In case of suboptimal response to these drugs, escalation to immunosuppressive and biological drugs may be necessary. Importantly, despite the best medical therapy, surgery may be necessary in a percentage of patients. The future is likely to see a number of new treatment options for people with ulcerative colitis with the potential for a more personalised treatment approach.

Ulcerative colitis (UC) is a relapsing and remitting inflammatory bowel disease (IBD) characterised by inflammation of the mucosa that begins distally and may extend proximally to involve the entire colon. UC has a bimodal age distribution with a peak incidence in the second or third decade and a second peak between 50 and 80 years of age. The aetiology involves interactions between environment, immune system, gut microbiome and a genetic predisposition to the disease. Ulcerative colitis presents with bloody diarrhoea, frequency, abdominal pain, fatigue and faecal incontinence.

The Montreal classification groups patients with UC, according to their maximum extent of disease, into E1 or proctitis (disease limited to the rectum); E2 or left-sided disease (distal to splenic flexure); and E3 or extensive colitis (disease extends proximal to splenic flexure). Patients with left-sided disease or extensive colitis are associated with increased risks of drug use, colectomy and colorectal cancer. In addition to the extent of disease, the main risk factors for colorectal dysplasia/cancer in UC include duration of disease; endoscopically or histologically active inflammation; presence of a post-inflammatory stenosis or polyps; family history of colorectal cancer; and associated primary sclerosing cholangitis (a chronic inflammatory disease of the bile duct that affects 3-7% of UC patients). Other extra-intestinal manifestations of UC include, in order of frequency, anaemia, arthropathy (axial or peripheral), cutaneous (erythema nodosum or pyoderma gangrenosum) and ocular (anterior uveitis or episcleritis), most of which reflect UC disease activity, with the exception of ankylosing spondylitis and peripheral polyarthritis.

In 2015, the Selection Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative made recommendations on therapeutic targets in IBD that were subsequently updated in December 2020 in the SPIRIT consensus. In summary, this consensus agreed that UC treatment targets should address a composite of clinical and endoscopic outcomes (potentially with the use of surrogate measures of inflammation, such as faecal calprotectin), in addition to the ultimate goals of addressing the impact on a patient's life (health-related quality of life, disability, and faecal incontinence), preventing disease extension, surgery, permanent ostomy, and dysplasia or cancer.

The severity of the disease is measured by the evaluation of clinical and biochemical parameters. Endoscopically, the Endoscopic Ulcerative Colitis Severity Index (UCEIS) is the only validated scoring system to assess severity, however, the Mayo score is commonly used in clinical practice due to its simplicity in application.

The future

There are a number of therapeutic targets being explored in the treatment of ulcerative colitis in various clinical stages to include sphingosine-1-phosphate receptor modulators (such as ozanimod and etrasimod), JAK inhibitors (such as upadacitinib), anti-leukocyte integrins (such as etrolizumab and abrilumab), monoclonal antibodies (such as mirikizumab) and faecal microbiota transplantation. These will potentially offer new options for the medical treatment of ulcerative colitis, but currently remain at the clinical trial stage.

It is likely that head-to-head studies will allow us to position the biologics correctly. As we gain a better understanding of the biological mechanisms that drive UC, it may become possible to find the right drug for the right person at the right time, while ensuring that the patient's broader goals (impact on quality of life, psychological and dietary support) are addressed.

Prof. Massimiliano Varriale

Varriale (proctologist): 'Stem cells can make an important contribution to the treatment of ano-vaginal fistulas. By using them, we can perform minimally invasive surgical techniques that avoid more important interventions, such as packing an ostomy".

Less invasiveness, shorter post-operative stay and better prognosis. These are the ingredients of the success that the surgical team of Professor Massimiliano Varriale, proctologist at the Sandro Pertini Hospital in Rome, has achieved through the use of stem cells. 'Stem cells can make an important contribution to the treatment of certain complications that can occur in patients suffering from chronic intestinal diseases,' explains Professor Varriale. By using them, we can perform minimally invasive surgical techniques that lead to improvement or even cure, avoiding more important and, above all, disabling surgeries for the patient, such as the packing of an ostomy'.

With stem cells fistula closure is minimally invasive

Thanks to the use of stem cells, Professor Varriale's surgical team has obtained excellent results in the treatment of fistulas that, in women suffering from chronic intestinal diseases, can appear in the ano-vaginal area. 'Such fistulas,' the proctologist explains, 'are difficult to manage and present a rather high risk of recurrence. The use of stem cells allows surgical techniques to close fistulas, whether anal-complex or ano-vaginal fistulas, in the most direct way, with excellent results. Thanks to this technique, patients can maintain normal intestinal function, avoiding the need to undergo surgery for an ostomy, which is much more complex and disabling, both in the short and long term'.

Stem cell harvesting

Stem cells are taken directly from the patient's body. "Fat is taken from those areas of the body that are richest in it," says Varriale, "such as the anterior abdominal wall, buttocks, hips, inner thighs. The fat obtained is microfiltered and a preparation characterised mainly by stem cells is obtained. The resulting hypofiller is then inoculated directly into the fistula, all in an outpatient setting. The autologous stem cell graft results in compression closure of the fistula, thanks to the formation of scar cells originating from the grafted stem cells'.

The study

As well as allowing the patient to return home within a few hours, this surgery also significantly reduces the risk of recurrence. "And should a recurrence occur,' the proctologist emphasises, 'there is no contraindication to performing the operation again, even after a short time. Professor Massimiliano Varriale is a forerunner of this minimally invasive surgical technique, so much so that he has been engaged in a scientific study on the subject for five years. "The research was conducted on a sample of women suffering from chronic intestinal diseases who developed ano-vaginal fistulas and underwent closure surgery with stem cells, closure certified by magnetic resonance examinations. The study, which has been ongoing for five years,' the specialist concludes, 'has offered very satisfactory results, which are close to publication.